Cardiovascular implications of glomerular filtration rate alterations beyond conventional chronic kidney disease classification

Chronic kidney disease (CKD) is a global health concern strongly associated with cardiovascular disease (CVD) and high mortality rates. Glomerular filtration rate (GFR) abnormalities, such as glomerular hyperfiltration (GHF) and selective glomerular hypofiltration syndrome (SHS), although not traditionally included in the CKD framework, share chronic inflammation as a pivotal mechanism driving systemic complications and CVD progression. In recent decades, GHF has gained substantial importance due to the high cardiovascular (CV) risk and mortality observed in populations within the highest tertiles of GFR, as determined by both estimation formulas (estimated GFR (eGFR)) and clearance (Cl) of exogenous substances. It is frequently observed in conditions such as obesity, diabetes, and metabolic syndrome. This hyperfiltration state is linked to endothelial dysfunction and CKD progression, often presenting with albuminuria, an independent marker of oxidative stress and CVD. SHS, on the other hand, involves the selective hypofiltration of medium-sized molecules (e.g. cystatin C) (Cys C), leading to proteomic alterations and the retention of pro-inflammatory molecules. This dysregulation intensifies systemic inflammation, atherosclerosis, and endothelial dysfunction, emphasizing SHS's role in CVD pathogenesis. The accuracy of CKD diagnosis is challenged by variability in eGFR methods, with formulas based on Cys C and creatinine (Cr) providing superior predictive value as biomarkers of risk in CKD and for detecting GFR abnormalities like GHF and SHS. Early identification and targeted management of these classical and non-classical GFR alterations may reduce the CVD burden and improve outcomes, underscoring the need for consensus definitions and multidisciplinary approaches to expand the CKD paradigm.